(2,4,6-Alkoxy)(3-pyrrolidino propyl) ketones

ABSTRACT

Novel aminoketones of general formula   in which each of R1, R2 and R3, which may be the same or different, represents a hydrogen atom or an alkyl group, each of R4 and R5, which may be the same or different, represents a hydrogen atom or an alkyl group or R4 and R5 together form, with the nitrogen atom to which they are bonded, a heterocyclic group with 5,6 or 7 ring atoms, optionally containing, in addition to the indicated nitrogen, a further hetero-atom which is sulphur oxygen or an additional nitrogen atom and n is 1, 2, 3 or 4; or an acid addition salt thereof, are provided having spasmolytic and/or vasodilatant properties.

United States Patent 1 Lafon 1 (2,4,6-ALKOXY)(3-PYRROLlDINO PROPYL) KETONES [75] Inventor:

[73] Assignee: Orsymonde, France [22] Filed: May 3, 1971 [21] Appl. No.: 139,894

Louis Lafon, Paris, France [30] Foreign Application Priority Data May 6, 1970 United Kingdom 21865/70 52 us. Cl ..260/326.5 J; 260/243 B; 260/2475 F; 260/268 1-1;260/293.71; 260/3097; 260/310 D; 260/570.5 0;

424/274 [51] Int. Cl C07d 27/06 [58] Field of Search 260/3265 J [451 July 15, 1975 Primary ExaminerDonald G. Daus Assistant Examiner-Jose Tovar [57] ABSTRACT Novel aminoketones of general formula 0R R,o -co(cn, ,.-N oR,

in which each of R R and R which may be the same or different, represents a hydrogen atom or an alkyl group, each of R and R which may be the same or different, represents a hydrogen atom or an alkyl group or R, and R together form, with the nitrogen atom to which they are bonded, a heterocyclic group with 5,6 or 7 ring atoms, optionally containing, in addition to the indicated nitrogen, a further heteroatom which is sulphur oxygen or an additional nitrogen atom and n is l, 2, 3 or 4; or an acid addition salt thereof, are provided having spasmolytic and/or vasodilatant properties.

4 Claims, No Drawings 1 2 (2,4,6-ALKOXY) (3-PYRROLIDINO PROPYL) R KETONES NC(CH.,),,-N R I} n The present invention relates to new aminoketone derivatives of phloroglucinol which are useful thera- 5 wherein n, R4 and Rsare as d fi d abovewith phlofly peutic agents. glucinol and an ether thereof of formula:

The present invention provides an aminoketone of eneral formula 1n 0R R 0 R. i R O CO(CH2),,-N Rs 2 5 CR3 3 wherein R,, R and R are as defined above, in an anhydrous solvent, in the presence of a stream of HCl gas, in which ea h f R1, R2 and 3, which y be the same at a temperature of from 5C. to the boiling point of the or different, represents a hydrogen atom or an alkyl l d group, preferably a C1-C5 alkyl group, n p rti ul r a b. hydrolysing the ketimine hydrochloride thus obmethyl or ethyl group; each of R and R which may rained,

be the same or different, represents a hydrogen atom Alternatively, the compounds of formula I and their or an alkyl group, preferably a C -C alkyl group, in acid addition salts can be prepared by replacing the reparticular a methyl or ethyl group, or R and R toaction of the nitrile of formula II with the phloroglucigether form, with the nitrogen atom to which they are nol of formula III by the condensation of a chloronitrile bonded, a heterocyclic group of 5, 6 or 7 ring atoms opof formula V with the phloroglucinol of formula III, and tionally containing, in addition to the indicated nitrothen condensing the amine of formula VI] with the gen, a further heteroatom, especially a sulphur, oxygen chloroketone thus obtained.

or additional nitrogen atom, unsubstituted or substi- As can be seen from the following equations, the altuted by alkyl, aryl, amino, aminoalkyl, hydroxyl, hyternative process (B) is equivalent to the first process droxyalkyl, anilide or N-substituted amidoalkyl groups; (A):

and n is l, 2, 3 or 4; and an acid addition salt thereof. because the reaction of NC(CH,,)NR,,R according to The compounds of formula l may be prepared acprocess A is replaced, in process B, by the succescording to the Houben-Hoesch reaction, which comsive reaction of the reactants NC(Cl-l ),,Cl and prises: HN(R R which correspond to the former reaction,

a. condensing an amino butyronitrile of formula f PrOCeSS B is mploye t iS preferable to hydrolyse the ketimine hydrochloride VIII which can be obtained under the same conditions as used in step (a) in process A, so as to prepare the compound of formula VI before condensing with the amine of formula VII. The reaction with the amine of formula VII is generally carried out at a temperature of from C. to the boiling point of the solvent used. If the solvent is dimethylformamid e, the condensation reaction is suitably carried out between 20 and 80C. over 2 to 20 hours.

Process B is more suitable than process A if it is desired to prepare a compound of formula l in which the heterocyclic structure NR R possesses substituents which are capable of either reacting with the phloroglucinol of formula III or of being destroyed during the formation of the nitrile of formula II.

The reactions of the nitriles of formulae II and V with the phloroglucinol of formula III are preferably carried out in an inert anhydrous solvent such as a nitrobenzene or a chlorobenzene.

The mononuclear heterocyclic structure NR R can contain, for example, the following substituents: linear or branched alkyl groups; phenyl groups; phenyl groups monosubstituted or polysubstituted by C -C alkyl radicals; hydroxy, hydroxyalkyl; amino; amino N- monosubstituted or disubstituted by C -C lower alkyl radicals, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, amidoalkyl, N-alkylated amidoalkyl, N- phenylamidoalkyl and N-arylamidoalkyl groups. In this specification, the term alkyl group is intended to cover both linear and branched hydrocarbon chains. Preferably, the alkyl groups contain from 1 to 5 carbon atoms. Preferred substituents carried by the ring NR4R5, include: CH2CH2OH, -'CH2CH2N(C2H5)2 and To prepare a compound of formula I in which process B is preferably'employed. Furthermore, to prepare a compound I in which -NR,R, is -N N- CH CONH it is generally preferable to condense w-chloro-2,6- dimethyl-acetanilide with a compound of formula I in which The acid addition salts which are suitable are, in particular, those of inorganic acids, especially hydrochloric, hydrobromic, hydriodic, sulphuric and phosphoric acids, and of organic acids such as oxalic, fumaric, maleic, malic, citric, ascorbic, cyclohexylsulphamic, benzoic, glutamic and aspartic acids.

The present invention also provides a therapeutic composition which contains, as active ingredient, at least one compound of formula I or a non-toxic acid addition salt thereof, in association with a physiologically acceptable carrier or diluent. These therapeutic compositions generally contain at most by weight of active ingredient, in combination with the usual excipients, such as isotonic solutions for injection or prefusion, talc, magnesium stearate as lubricants, sugars, lactose and glucose, for the preparation of tablets and dragees, as well as capsules and gelatine-coated pills; galenical excipients used in the manufacture of suppositories are also suitable.

Preferably, the preparations for oral use contain from 0.01 to 0.05 g. of active ingredient which is administered to the patient, for example 3 to 5 times daily during the period of treatment.

The compounds of formula I and their non-toxic acid addition salts have proved particularly valuable in therapy as vasodilators and/or spasmolytic agents, as the tests given below indicate.

The following Examples further illustrate the present invention.

EXAMPLE 1 (2 ,4,6-Trimethoxy-phenyl 3 -pyrrolidino-propyl ketone hydrochloride HCl OCH

Introduce 33.6 g (0.2 mol) of 1,3,5- trimethoxybenzene and 100 ml of chlorobenzene into a 500 ml threeneck flask with stirrer, hydrochloric acid bubbler and condenser. Stir to dissolve and add 27.7 g of 4-pyrrolidinobutyronitrile. Cool to about 15-20C and bubble hydrochloric acid gas in for 4 hours. Cool to about 5C and add 200 cm of water. Stir. Decant the aqueous layer, wash again with 150 cm of water. Combine the aqueous layers, drive off the traces of chlorobenzene by distilling 150 cm of water, and heat under reflux for one hour. Cool and render alkaline by means of 60 ml of sodium hydroxide solution of 36 Baume. Extract with twice 100 ml of ether. Wash the ether with 100 ml of water. Dry the ether over sodium sulphate and slowly run in 50 ml of 5 N hydrogen chloride solution in ether, at the boil. Cool in ice. Filter, wash with ether and dry in a vacuum oven. 33.6 g of crude product are obtained. Recrystallise from 200 ml of isopropanol in the presence of 3 SA carbon black. Filter. Wash and dry in a vacuum oven.

26.9 g of a white, crystalline water-soluble powder are obtained.

Yield 39.2%

Instantaneous melting point 192-l93C.

EXAMPLE 2 (2,4,6-Trimethoxy-phenyl) (2-N,N-diethylamino-ethyl) ketone hydrochloride Hydrochloride Total synthesis equation OCH +H CO Houben Hoesch H CO OCH a. Preparation of the nitrile NC-CH CH N(C H cf. J. Am. Chem. Soc. 67 1945) 1472; J. Am. Chem. Soc. 70. 4020. 4620. (1948).

0.160 Mol (21.7 g) of l-chloro-Z-diethylaminoethane dissolved in 85 cm of pure ethanol is added dropwise, whilst stirring, to 0.178 mol (11.6 g) of K--C N in 40 cm of water.

The mixture is heated under reflux for 20 hours. The cooled solution is filtered, the precipitate is washed 8.26 g of product are obtained.

Yield 48%. The IR spectrum shows the appearance of a N E C band at 2240 cm and the disappearance Of the CCl bands between 660 and 760 cm".

b. Condensation of the nitrile with trimethoxybenzene cm of chlorobenzene are introduced into a cm three-neck flask. 20 cm thereof are distilled to remove traces of water. The residue is cooled in an ice bath and 11.8 g of trimethoxybenzene and 8.26 g of diethylaminopropionitrile are added, and HCl gas is bubbled through for 6 hour's4O minutes. At the start of bubbling in HCl, a gelatinous precipitate forms, which redissolves after 1 hour.

65 cm of water are added whilst continuing to cool by means of an ice bath. The emulsion is decanted. The chlorobenzene is washed with 30 cm of water. 30 cm of the aqueous phase are distilled to eliminate the chlorobenzene, and the solution is heated to the boil for 1 hour.

On cooling, a black precipitate appears, which is filtered off. 40 cm of sodium hydroxide solution, to bring the pH to 11, are poured in so as to liberate the base. The base is extracted with 2 X 40 cm of ether. The ether phase is dried overnight over Na SO The mixture is filtered. 65 cm of a solution of hydrogen chloride in ether (about 1.1 N) are poured into the ether solution under reflux, whilst stirring.

The mixture is cooled in an ice bath, and a pinkishorange paste precipitates, which is taken up in 50 cm of isopropanol 200 cm of ether. Pink crystals are obtained.

The crystals are recrystallised from a mixture of 50 cm of ethyl acetate and 10 cm of isopropanol, using charcoal (2 g).

OCH

OCH

6.4 g of a water-soluble crystalline product are obtained.

Yield: 32%.

Melting point: 134-135C.

IR spectrum correct.

% C1 11.05, theoretical C1 10.70.

Purity 97%.

EXAMPLE 3 (2,4,6-Trimethoxy-phenyl) (4-diethylamino-butyl) ketone hydrochloride OCH CHO

OCH

a. w-Chloro-valeronitrile 74.1 g of KCN (1.14 mol) and 100 ml of water are introduced into a 1000 ml Erlenmeyer flask with condenser and dropping funnel; the mixture is heated until the potassium cyanide has completely dissolved. 100 ml of ethanol are then added. 171.5 g (1 mol) of chlorobromobutane dissolved in 100 ml of ethanol are poured in rather rapidly from the dropping funnel. The mixture is heated under reflux for 22 hours; a yellow solution is obtained and a copious precipitate forms (KBr). The mixture is filtered. The water and the alco- CHO hol are evaporated. The oil which remains is distilled in vacuo.

Weight 53.22 g

Yield: 45.2%

b. Diethylamino-S-valeronitrile.

200 ml of acetone, 24.1 g of diethylamine (0.33 mol) and 42 g of sodium iodide (0.28 mol) are introduced into a 1000 ml Erlenmeyer flask with condenser, magnetic stirrer and dropping funnel.

The mixture is heated under reflux until the Nal has dissolved. 32.9 g of 5-chloro-valeronitrile (0.28 mol) are poured in dropwise from the dropping funnel. The mixture is heated under reflux for hours. A copious white precipitate forms. The mixture is cooled and the acetone is evaporated. The residue is taken up in 100 ml of water 60 ml of sodium hydroxide solution (pH 11). A red oil is obtained, which is extracted with 100 ml of ether. After having washed the aqueous phase with 100 ml of ether, the ether phases are combined. The ether is evaporated. The residue is distilled in vacuo. 29.78 g of 5-diethylamino-valeronitrile are obtained.

Yield: 69%.

c. Condensation of the nitrile with 1,3,5-trimethoxybenzene The Houben-l-loesch reaction of 33.6 g (0.2 mol) of trimethoxybenzene and 29.7 g (0.19 mol) of 5- diethylaminovaleronitrile in 150 ml of chlorobenzene, followed by recrystallisation of the crude product obtained from the mixture of 80 ml of isopropanol and 240 ml of ethyl acetate yields 24.71 g of (2,4,6-

0 trimethoxy-phenyl) (4-diethylamino-butyl) ketone hydrochloride, which is soluble in water.

Yield: 36.1%. IR spectrum correct. Cl identical to the theoretical value. Melting point: 156C.

EXAMPLE 4 [2,4,6-Trimethoxy-phenyl] [(4-Bhydroxyethyl-piperazino)methyl] ketone dihydrochloride OCH Co-CH, -N N- CH -CH,-0H.2Hc1

OCH

a. (2,4,6-Trimethoxy)-w-chloroacetophenone A stream of HCl gas is passed into a reactor containing 750 cm of anhydrous chlorobenzene, 1 mol of trimethoxybenzene and 1 mol of chloroacetonitrile 'until the mixture is saturated. The ketimine hydrochloride obtained is filtered off, and this hydrochloride is then hydrolysed with 1 litre of water at the boil for 1 hour. The mixture is cooled and the precipitate of (2,4,6-trimethoxy)-w-chloroacetophenone is filtered off. It is dried with P 0 under reduced pressure.

Melting point: 92C.

Yield: 74%.

b. [2 ,4 ,6-Trimethoxy-phenyl] (4- B-hydroxyethylpiperazine) methyl] ketone dihydrochloride.

A mixture of 0.11 mol of (2,4,6-trimethoxy)-wchloroacetophenone, 0.10 mol of (N-2-hydroxyethyl)- piperazine and 0.11 mol of dry K CO in 60 ml of anhydrous DMF is stirred at 20C for 15 hours and at C for 1 hour 30 minutes.

The cooled solution is filtered. The precipitate is washed with DMF. ml of ether are added and 40 ml of 5 N HCl-ether are poured in. An oil forms. The DMF is decanted and this oil is taken up in 80 cm of ether. A precipitate is obtained. Recrystallisation from 550 ml of absolute ethanol.

28.03 g of a water-soluble product are obtained.

Yield: 68.19%

Melting point: 146C.

EXAMPLE 5 [2,4,6-Trimethoxy-phenyl] [4-( 2-diethylamino-ethyl )-piperazinomethyl ketone trihydrochloride OCH l C H CH O CO-CH N N- CH CH N 2 5 .3 l-lCl v OCH a. Z-Diethylamino-ethylpiperazine A solution of 40.34 g (0.166 mol) of 2,4,6-trimethox- 12.51 g (0.0923 mol) of l-chloro-2-diethylamin0- ychloroacetophenone in 150 ml of dioxane is poured ethane are poured dropwise into a solution, maintained dropwise into a solution of 43 g (0.5 mol) of anhydrous at 6070C, of 23.9 g of anhydrous piperazine (0.277 piperazine in 150 ml of dioxane (the temperature being mol) in 100 ml of dioxane. A precipitate of piperazine kept at 60-70C). The mixture is heated under reflux hydrochloride forms. for 4 hours.

The mixture is heated under reflux for 4 hours after A precipitate of piperazine hydrochloride forms, and the end of the introduction of the chloro derivative, is filtered off. The dioxane is evaporated. The residue and filtered. The dioxane is evaporated. The residue is is taken up in the minimum amount of dilute sodium taken up in a dilute sodium hydroxide solution. The sohydroxide solution. The solution is extracted with chlolution is extracted with chloroform, the extract is dried roforrrr Th hl f is evaporated, The residue is O 2 4 and filtered, and the chloroform iS P taken up in ether and the dihydrochloride is precipirated. The residue is taken up in ether and the product tated by means of a solution of hydrogen chloride in is precipitated in the form of a hydrochloride by means th of a solution of hydrochloride in ether. The trihydro- Recrystallisation from methanol yields 35.15 g of(2,- chloride is recrystallised from a mixture of methanol 4,6-trimethoxy phenyl)(pipol-azinomethyl)ketone ethyl acetate; 20 g of product are obtained. h d hl id Yield: 86%. Yield: 57.6%. b. [2,4,6-Trimethoxy-phenyl][4-(2-diethylamino- Melting point; decomposes at 200C. ethyl)piperazinomethyl]ketone trihydrochloride I was ibl t i l t th b 18.26 g (0.0747 mol) of (2,4,6-trimethoxy)-co M l i point f the base; 9 chloroacetophenone, 10.31 g (0.0679 mol) of K CO and 0.0679 mol of 2diethylamino-ethyl-piperazine in 50 ml of anhydrous dimethylformamide are stirred for EXAMPLE 6 bi 24 hours at ambient tem erature (l525C).

The precipitate of KCl l/hich is formed is filtered off on the procedur? ndlcated Example and washed with DMF. The trihydrochloride is precipii P h g l gFi 5 tated from its base, dissolved in DMF, by means of a soplperazmqacemllm lution of hydrogen chloride in ether. The product is re pherlyl)(plperazmomethynketone dlhydrochlonde crystallised from a mixture of methanol and ethyl ace- Obtamed' tate.

17 g of product are obtained.

Yield: 43.3%. EXAMPLE 7 IR spectrum correct. [2,4,6-Trimethoxy-phenyl][4-(N-2,6-dimethyl- Cl identical to the theoretical percentage. phenylacetamido) piperazinomethyllketone Melting point: 170C. dihydrochloride.

OCH

H CO co cH CH C0NH .ZHCl

ocH 3 EXAMPLE 6 A mixture of 23 g (0.078 mol) of (2,4,6- (2,4,6-Trimethoxy-phenyl)(piperazinomethyl)ketone trimethoxyphenyl) (piperazinomethyl) ketone, 17.78 g dihydrochloride (0.09 mol) of 2,6-dimethylw-chloroacetanilide and CCH H3CO COCH2 N NH .2 HCl OCH 11 12.42 g (0.09 mol) of K CO in 50 ml of DMF is stirred at ambient temperature (l5-25C) for 24 hours. The mixture is filtered, and the precipitate is washed with 20 ml of DMF and then twice with 20 ml of ether at a 7 EXAMPLE 8 (2,4,6-Triethoxyphenyl)(3-diethylaminopropyl) ketone hydrochloride triethoxybenzene, 92 ml of nitrobenzene, 25.9 g (0.185 mol) of 4-diethylaminobutyronitrile and 55.5 g (0.416 mol) of aluminium chloride into a 500 ml three-neck flask, with stirrer, hydrochloric acid bubbler and condenser. Cool the contents to' l520C and bubble hy drogen chloride in for 6 hours. Pour the solution into 450 ml of water ice. Decant the aqueous layer. Distil 100 cm of water to eliminate the nitrobenzene and heat under reflux for 1 hour. Cool and render alkaline with 250 ml of sodium hydroxide solution. Extract with three 160 ml portions of ether. Wash the ether with 2 portions of 120 ml of water. Dry the ether over sodium sulphate. At the boil, run in 55 ml of 5 N hydrogen chloride in ether. A black paste is obtained. This is dissolved in hot acetone ml) and 400 ml of ether are added dropwise, whilst stirring. The mixture is filtered, and the product is washed with ether and dried in an oven under reduced pressure. 24.15 g of grey-violet crystals are obtained. Recrystallise from ml of ethyl acetate in the presence of carbon black. Filter, wash and dry in an oven under reduced pressure.

19.5 g of violet water-soluble crystals are obtained.

Yield: 27.5%

Instantaneous melting point: 122C.

EXAMPLE 9 (2,4,6-Triethoxyphenyl)(3-pyrrolidinopropyl) ketone hydrochloride OC H a. preparation of triethoxybenzene OH OC H 72 g of dry phloroglucinol, 268 g of K CO and 460 ml of anhydrous acetone are introduced into a 2 litre flask equipped with thermometer, stirrer and dropping funnel. The mixture is heated under reflux. The diethyl sulphate is poured in dropwise. After introduction of the (C H SO;,, the mixture is heated under reflux for 30 minutes. A brown paste is obtained. 250 ml of a mixture consisting of 1 10 ml of 20% strength ammonia and ml of water are now added.

After distilling the acetone, 1 litre of water is added. The residue is extracted with 1350 ml of methylene chloride. The whole is washed with 4 X 250 m1 of 1 N sodium hydroxide solution. The methylene chloride solution is dried over Na SO the methylene chloride is evaporated and the triethoxybenzene is distilled in vacuo.

56.22 g of 1,3,5-triethoxybenzene are obtained.

Yield: 47.05%

Boiling point 128/1.7 mm

b. A stream of l-lCl gas is bubbled into a solution of 200 m1 of chlorobenzene containing 0.225 mols of triethoxybenzene and 0.225 mol of 4-pyrrolidinobutyronitrile, until the solution is saturated. A copious precipitate of ketimine hydrochloride forms, and is filtered off. This product is hydrolysed with 220 ml of water at the boil for 1 hour. The base is liberated by neutralising the aqueous solution with sodium hydroxide solution. The base is taken up in 200 ml of ether and dried over Na SO The hydrochloride is precipitated by means of 60 ml of a 2.6 N solution of HCl in ether. The hydrochloride is recrystallised from 100 ml of ethyl acetate 70 ml of isopropyl alcohol. The product is soluble in water.

37.6 g of (2,4,6-trimethxy-phenyl)(2-N,N-diethylaminoethyl)ketone hydrochloride are obtained.

Yield: 43.3%.

Melting point: 171C.

EXAMPLE a. Preparation of 2 -isopropylamino-phloroacetiminophenone hydrochloride b. Preparation of (2,4,6-trihydroxyphenyl isopropylaminomethyl) ketone hydrochloride.

CH, HO CCH2-NHCH .HCl

12 g (0.04 mol) of 2'-isopropylaminophloroacetiminophenone in 50 ml of water and 25 ml of concentrated HCl are heated to the boil in a 250 m1 ground-neck flask.

Boiling is continued until the product has dissolved completely, which requires about 5 minutes.

The mixture is cooled and the product is filtered off and recrystallised from an ethanol-ether mixture.

8.5 g (81%) of creamy-White crystals are obtained.

Melting point: 248-250C.

The product obtained is soluble in water and in alcohols.

The hydrochloride of (2,4,6-trihydroxyphenyl) (isopropylaminomethyl)ketone is soluble in methanol and ethanol, very soluble in water, but insoluble in ether and in ethyl acetate.

EXAMPLE 1 l (2,4,6-Trihydroxyphenyl)( 3-morpholinopropyl)ketone hydrochloride 12.6 g (0.1 mol) of anhydrous phloroglucinol and cm of nitrobenzene are introduced into a 250 cm three-neck flask equipped with reflux (condenser), bubbler and stirrer.

The temperature is adjusted to between 15 and 20C, and is maintained throughout the time that the hydrochloric acid is passed.

15.4 g (0.1 mol) of morpholinobutyronitrile are added and a stream of hydrochloric acid is passed for 8 hours. I

cm of water are then added until the precipitate has dissolved in the cold.

The nitrobenzene layer is decanted and washed with 50 cm of water, which are added to the aqueous layer. About 50 cm of the aqueous layer are distilled, and the remainder is refluxed for 1 hour.

The mixture is cooled to about 0C.

A precipitate appears.

This is filtered off, washed with 30 cm of iced water, drained, and dried in vacuo over potassium hydroxide. It is recrystallised from a mixture of 80 cm of ethanol and 20 cm of water, in the presence of charcoal.

1 1.8 g of a white, slightly cream, powder which is $01- uble to the extent of 4% in water are obtained.

Yield: 37.2%

Instantaneous melting point: 246252C, with decomposition.

On concentrating the mother liquors from the first filtration to one-third and treating them as above, 0.9 g of product of identical properties to the above are obtained, thereby raising the yield to 40%.

EXAMPLE l2 (2 ,4 ,6-Trimethoxyphenyl 3 diethylaminopropyl)ketone hydrochloride OCH OCH

15 16 Introduc 16 g -l of trimethoxybenzene, 60 19.9 g (yield 55.4%) of a crystalline, white, slightly g of nitrobenzene and 30 g of aluminum chloride into Cream, powder are bt i d, a threeneck flask equipped with stirrer, reflux con- Instantaneous l i i t; 210 215C denser and means of bubbling in HCl. Cool to about C. Run in 14 g (0.1 mol) of diethylaminobutyroni- 5 trile. Saturate with a stream of dry HCl gas whilst maintaining the mixture at about C for 6 hours. EXAMPLE 14 The mixture is poured into 250 cm of water, the (2,4,6-Trimethoxypheny1)(3-piperidinopropyl)ketone aqueous layer is decanted and washed with ether, and hyd chl rid OCH CO CH Hsco 2):; N HCl OCH the aqueous layer is again decanted and heated under This compound is obtained in a yield of 40% by using reflux for 1 hour. It is cooled and rendered alkaline, to the conditions described in Example 13 and starting pH 12, with sodium hydroxide solution. from piperidinobutyronitrile.

The base is extracted with ether, the ether layer is Melting point: 197C. dried with sodium sulphate and filtered, and the hydro- The results of pharmacological and clinical tests carchloride is then precipitated by means of a solution of ried out with the products described above have been hydrogen chloride in ether. It is filtered off and recryssummarised below. tallised from isopropanol. The product of Example 1, namely (2,4,6- 20.7 g (yield 59.5%) of a violet crystalline powder trimethoxyphenyl) (3-pyrrolidinopropyl)ketone hydroare obtained. chloride, has given the following effect in animals.

Instantaneous melting point (Kiifler): 15 lC. Acute Toxicity When administered intravenously to mice, the LD is 80 :t 4.6 mg/kg. At this dose, administered intravenously, sedation, haematuria, vasodilatation and hypo- EXAMPLE 13 thermia (slight 0.7C) was observed in mice. The an- (2,4,6-Trimethoxyphenyl)(3- imals given a dose of mg/kg intramuscularly did not morpholinopropyl)ketone hydrochloride display any symptom.

OCH

OCH

Introduce 16.8 g (0.1 mol) of 1,3,5- Peripheral Vasodilatatory Properties trimethoxybenzene, 60 g of nitrobenzene and 30 g of When injected directly into the femoral artery, the aluminium chloride into a 250 cm three-neck flask product increases the femoral flow rate from a dose of equipped with stirrer, reflux condenser and means of l mg/animal upwards. bubbling in HCl. Cool to about 15C. Run in 15.4 g When injected intravenously into 3 dogs, atadose of (0.1 mol) of morpholinobutyronitrile. Saturate with a 8 g/kg (one-t nth of th intravenous LD in mice), stream of dry l-ICl gas whilst keeping the mixture at the product increases the femoral arterial flow in four about 20C for 6 hours. Pour into 250 cm of water and tests out f fi stir. Decant the aqueous layer and wash it with ether. o a i l i t d d l d i i i f 20 Decant. Heat the aqueous layer under reflux for 1 hour. mg/kg to f dogs, i i f d that n the animals C001 a render alkaline t0 P 12, with Sodium y play an increase in the femoral flow. This increase mandroxide solution. Extract the base with ether. Dry the if t it lf rapidly and lasts about 1 hour. ether layer over sodium sulphate and filter. Precipitate Study f the c b vasodilatatory properties the hydrochloride by means of a Solution of hydrochlo' When injected into the internal carotid, the product ride in ether. Filter off and recrystallise from amixture moderately increases the carotid fl f 1 mg/anh of absolute ethano 31 the the mal onwards. The results relating to the product of Expresence of charcoal. Filter, allow to crystallrse. Filter. ample 1 were compamd i those f acetylcholine Wash with absolute ethanol. Dry. r T ble I),

TABLE I Product Dose A.P. A of flow Acetylcholine 10 pg 150 20 pg 0 175 Product of 10 mg 0 33 Example I mg 0 33 In Table I and in the following tables, the differences expressed as a percentage A% are expressed relative to the animal undergoing experimentation, which serves as a reference standard for itself; the normal value is recorded, and the product is then injected and the A% is thus obtained as the relative difference. This method is made necessary because of the various parameters involved in the absolute value in various animals, however carefully these may be selected.

In Table I and the following tables, the arterial pressure abbreviated A.P., corresponds to the difference between the normal arterial pressure of the animal un dergoing experimentation, before injection of the product, and the arterial pressure observed after injection.

When injected intravenously at a dose of 8 mg/kg (one-tenth of the intravenous LD in mice) the product increases the carotid flow or the cerebral artery flow in two experiments out of three, for l0 minutes.

(2,4,6-Trimethoxyphenyl)(2-diethylaminoethyl)ketone hydrochloride (Example 2b) has an LD in mice, when injected intravenously, of 70 mg/kg. This product does notv display a peripheral vasodilatatory effect in dogs at doses of up to 7.5 mg/kg administered by perfusion for 45 minutes.

On the other hand, it possesses antispasmodic properties as regards isolated organs possessing a muscular action; in the case of the intestine of dogs, in situ, it blocks, at. doses of 3 to 5 mg administered intravenously, the spasms caused by barium chloride.

(2,4,6-Trimethoxyphenyl)(4- diethylaminobutyl)ketone hydrochloride, the product of Example 3c, has an LD of 46 mg/kg when administered intravenously to mice. It is not a vasodilatator, but it is a muscular action antispasmodic in vitro and in vivo.

The dihydrochloride of (2,4,6-trimethoxyphenyl)[4- B-hydroxyethyl-piperazino)methyl1ketone, namely the dihydrochloride of the product of Example 40, has an LD of I90 mg/kg when administered intravenously to mice. It displays a peripheral vasodilatatory action on the femoral artery flow after intravenous injection of 5 mg/kg into dogs, perfused in 5 minutes.

The product of Example 8, (2,4,6-triethoxyphenyl) (3-diethylaminopropyl)ketone hydrochloride, has an LD of 35 mg/kg when administered intravenously to mice. It was administered to six dogs, 5 times intravenously at doses of 3 mg/kg (three tests) and of 5 mg/kg (two tests), and once intraduodenally at a dose of mg/kg.

The results listed in Table 11 below show that the product of Example 8 exerts a peripheral vasodilatatory effect without a side-effect on the cardiac frequency.

The product of Example 9b, (2,4,6-triethoxyphenyl) (3-pyrrolidinopropyl)ketone hydrochloride, has an LD of 60 mg/kg when administered intravenously to mice, and proves to be a vasodilator, as is shown by the results of experiments carried out in dogs, these experiments being listed in Table III below.

The femoral or cerebral dilatation effect reaches its 5 maximum 2 minutes after the start of the perfusion and then diminishes, disappearing, when the perfusion has stopped, within a period of time which is markedly greater than 5 minutes.

(2,4,6-Trihydroxyphenyl)(isopropylaminomethyl)ketone hydrochloride, the product of Example 10b, has an LD of 475 mg/kg when administered intravenously to mice. At this dose, the treated animals displayed the following symptoms: sedation and piloerection. In animals which receive a dose of 240 mg/kg, administered intramuscularly, of this product, a hypothermy of -2.8C was observed and there was no change in the behaviour of the reflexes.

Study of the B-Stimulant Properties 1. Uterus of female rat in oestrus.

A. Isolated uterus:

At a dose of 47 mcg/ml, the product does not modify the spontaneous peristalsis (eight organs).

B. Uterus in situ:

When administered intravenously at a dose of 47 mg/kg (one-tenth of the intravenous LD in mice), the product reduces the amplitude and frequency of the spontaneous contractions in five tests out of six. In an average of the five tests, the peristaltic index is reduced by 47%.

The effect most frequently manifests itself in less than 5 minutes.

Return to normal varies greatly from one test to another: 44 minutes, 20 minutes,- 18 minutes, 26 minutes, 4 minutes.

2. Isolated auricle of a guineapig.

At doses of 0.01 to 1,000 meg/ml, the product no longer exerts any inotropic or positive chronotropic effect. At these doses, it no longer has a B-blocking effect.

3. Cardiac haemodynamic behaviour is anaesthetised dogs.

The product of Example 10b was injected intravenously into 2 dogs at a dose of 47.5 mg/kg (l/10 of the intravenous LD in mice). It does not behave as a ,B-stimulant. The coronary flow is slightly increased.

For the product of Example 12, an LD of 68 i 4 mg/kg (61 to 76 mg/kg) was found for intravenous administration to mice.

The following symptoms were observed Sedation, haematuria, peripheral vasodilatation even at non-toxic doses; death occurs through respiratory failure.

No symptom was observed in animals which had received 34 mg/kg administered intramuscularly, and in particular the behaviour and reflexes of the animals are normal and no tranquilising or analgesic effect was detected.

Antispasmodic Properties 1. In vitro A. Rat duodenum Organs at rest At a dose of 100 meg/ml, a sharp drop in the tonus of the organs takes place. Towards Barium Chloride It exerts an antispasmodic effectproportional to the dose, and reversible through washing.

19 The active dose, AD which was evaluated in the same way as the LD is about 2.8 ug/ml. The musculotropic activity of this substance is close to that of papaverine.

vasodilatation, lachrymation, excitation followed by sedation, and haematuria.

The animals which received 68 mg/kg administered intramuscularly show slight sedation and a slight hypo- Against Acetylcholine thermy (0.3C).

It exerts an antispasmodic effect proportional to the Antispasmodic Properties dose. The AD is about 35 ug/ml. On these organs, the l. Intestine AD of papaverine was 4 ug/ml. A. Isolated Duodenum of a Rat The neurotropic activity of the product is thus mark- It exerts an antispasmodic effect, proportional to the edly less than its musculotropic activity. dose, against barium chloride. The AD 3.8 #g/ml- B. Guineapig Ureter It exerts an antispasmodic effect against acetylcho- Even at a dose of 1 mg/ml, the substance does not afline, proportional to the dose, but at higher doses than fect the tonus of the organs; it reduces the peristaltoin h Case Of barium Chloride The 50 19 M-g/ genic effect of barium proportionately to the dose; B. Guineapig Ileum in Situ 25% at 10 pg/ml At a dose of 14 mg/kg administered intravenously 60% at 50; g/ml (one-tenth of the intravenous LD in mice), it reduces 80% at 100 ,ug/ml or stops the spontaneous intestinal peristalsis. As an av- 100% at 1 mg/ml erage of 5 tests, the peristaltic index is reduced by 67%.

C. Uterus of Rat in Oest The effect is immediate and continues for 10 to 30 min- At a dose of7 LLg/ml, it r d ce th spontaneous i- 2O utes in 3 tests, and for more than 50 minutes in the stalsis in three tests out of six after a time of contact of other 2 tests- 15 minutes. As regards the arterial pressure, the product either 2. In Vivo has a slight hypertensive effect 15% to 25%) or A. Guineapig Ileum in Situ produces a bi-phase effect: transient hypotension, fol- At a dose of 7 mg/kg administered intravenously 25 lo e by Slight hyp i t0 (one-tenth of the intravenous LD in mice), it moder- 2. U eter ately reduces the spontaneous peristalsis. On average, A. Isolated Ureter Of a Guineapig in five animals the peristaltic index is reduced by 58% It is inactive at a dose of 100 ug/ml: it reduces the for 10 to 20 minutes, and in the case of one of the aniperistalsis caused by barium chloride by 40% at 250 mals, for over an hour. Lg/ml and by 95% at SOOug/ml.

A slight hypertensive effect is observed during the in- B. Dog Ureter in Situ j cti n, When injected into 3 dogs at a dose of 14 mg/kgad- B. Dog Ureter in Situ ministered intravenously (one-tenth of the intravenous At a dose of 7 mg/kg administered intravenously, it LD in mice) it reduces the pressure in the"high presreduces the pressure by 43 to 73% in the high pressure 35 r r r 0 for 10 to 50 minu s n in ureter and by 31 to 73% in the low pressure ureter for h l pr r ureter to 63 f r 0 o 45 less than 10 minutes in two tests, and for more than minUteS- minutes in a third test. The effect on the arterial pressure and on the cardiac Peripheral Vasodilatator Properties frequency is nil. Respiration is slightly speeded up dur- When injected intra-arterially or intravenously (7 4O ing injection of the product.

mg/kg), it produces a long-lasting (8 to 30 minutes) in- Choleresis crease in the femoral arterial flow. In anaesthetised rats, the product of Example 13 at Effect on Choleresis a dose of 14 mg/kg administered intravenously (one- At a dose of 7 mg/kg administered intravenously in tenth of the intravenous LD in mice) exerts a slight rats, it produces a slight hypercholeretic effect (30%) choleretic effect (+36%) for 45 minutes. The cholerfor 75 minutes. The choleretic index is 40. etic index is 34.

In the case of the product of Example 13, an LD of Peripheral Vasodilatation Studied in Dogs 140 i 8 mg/kg is found on intravenous administration These results are reported in Tables IV and V. to mice, with the following symptoms: peripheral 50 l. Intra-Arterial Injection TABLE IV Femoral Dose A of A of Dose of A of A of Test flow, femoral femoral papafemoral femoral No.

ml/ flow resistance verine flow resistance minute 15 100 mcg 0 0 10 mcg +29 22(1' I06 14 1 mg +43 29(l) 100 mcg +35 -26(l) l5 l0 mg +106 5i (1') 1 mg +200 -66 (89") 46 100 mcg +13 I2 (30'') 10 mcg 0 0 114 46 l mg +22 l8(l') r00 mcg +12 ll(l') 36 10 mg -43 (4') 1 mg +28 26 (4') 2. Intravenous Injection TABLE V 7 Dose Method of Femoral A of A of Duration mg/kg administration flow femoral femoral ml/minute flow resistance 14 Injection in 4 mins 50 20 23 8 mins 14 Injection in 2'30 37 51 38 20 mins TABLE V Continued Dose Method of Femoral A of A of Duration mg/kg administration flow femoral femoral ml/minute flow resistance 14 Injection in 3'30 23 105 56 6 mins" 14 Injection in 3' 38 68 40 45 mins 14 Injection in 3 68 29 26 45 mins I, l4 Perfusion in 36' 73 3l 24 Duration of perfusion l4 Perfusion in 30' 67 9 followed by followed by 39 64 This product exerts a remarkable peripheral When administered venously to animals at a dose vasodilatation effect; the arterial pressure does not vary.

Antispasmodic Properties 1. In Vitro A. Rat Duodenum Against barium chloride this product exerts an antispasmodic effect proportional to the concentration. The effective dose 50 (AD is about 2.5 pug/ml. The musculoit'ropi'c antispasmodic activity of this substance is similar to that of papaverine.

Against acetylcholine, it exerts an antispasmodic effectpr'o'portional to the dose. The AD is about 25 #g/ml The musculotropic activity of the product is thus about times greater than its neurotropic activ ity.

B. Guineapig Ureter When administered preventively, it reduces the contraction effect of barium chloride by about 75% at a concentration of 100 Lg/ml, and by about 40% at a concentration of 50 mcg/ml. The barium chloride only recovers its initial effect after 2 or 3 washes.

2. In Vivo A. Guineapig lleum in Situ At a dose of 5 mg/kg administered intravenously (one-tenth of the intravenous LD in mice), it moderately reduces the spontaneous peristalsis. At an average of five animals, the peristaltic index is reduced by 68%, for 10 minutes in two cases and for 30 to 45 minutes in the other three cases.

A transient hypotensive effect is observed during injection.

B. Uterus of Female Rat, in Situ of 5 mg/kg, it moderately reduces the uterine peristalsis. This effect starts between the 7th and 20th minute following injection and lasts 30 to 120 minutes.

C. Dog Ureter in Situ At a dose of 5 mg/kg administered intravenously, it lowers the pressure in the high pressure ureter by 16 to 33% in two tests, and does not change it in the third test. The pressure in the low pressure ureter is not reduced in any of the cases.

No effect on the arterial pressure is observed. Peripheral Vasodilatator Properties When injected intra-arterially or intravenously (5 mg/kg) it produces a long-lasting increase in the femoral arterial flow.

Action on Choleresis In rats, at a dose of 5 mg/kg administered intravenously, it exerts a slight hypercholeretic effect (40%) between the 15th and 90th minute following injection.

The products according to the invention have proved valuable in clinical practice in the treatment of spasms.

migraines and circulatory disturbances.

In man, excellent results have been obtained in the treatment of gastro-intestinal spasms when using the derivatives corresponding to Examples 2b and 3c at a dose of 0.02 to 0.04 g per cachet or capsule taken three to 5 times daily.

Equally, the product of Example 10b has been administered to a man at a dose of 10 centigrams, this dose being administered 4 to 6 times daily in the form of cachets or tablets.

The product of Example 12 has been administered in clinical practice by injection (isotonic injectable ampoules containing 2 mg of active principle) for the treatment of arteritis, especially as a peripheral Vasodilatator.

The product of Example 13 has given good results in the treatment of nephritic colics in man. It has been administered in the form of a cachet or tablet containing 0.02 to 0.05 g of active principle, at the rate of 3 to 4 cachets or tablets per day.

In man, the product of Example 14, used as isotonic injectable ampoules containing one or two milligrams, and as tablets, cachets or capsules containing 0.01 g, has given excellent results in the treatment of nephritic colics.

TABLE II Arterial Pressure Cardiac Frequency Flow of the femoral artery Flow of the cerebral artery relarela- A rela- Com- A relative to tive to Method Comtive to parison tive to fire comthe com- Dose of parison the comvalue, the com- Companparison Resis- Compariparison Resismgladminivalue parison beat/ parison son value value tance son value value Lance kg stration mm Hg value minute value ml/mm (mm) ml/min (mm) 3 Intra- I -9 200 13 46 +36(2') 33 TABLE II Continued Arterial Pressure Cardiac Frequency Flow of the femoral artery Flow of the cerebral artery A rela- A rela A rela- Com- A relative to tive to Method Comtive to parison tive to the comthe com- Dose of parison the comvalue, the com- Compariparison Resis- Compariparison Resismg/- admini' value parison beat/ parison sb'n value value tance son value value tance kg stration mm Hg value minute value rnl/min (min) ml/min (min) venous 3 lntra- 150 +20 150 6 52 +46(25 27 venous perfussion 3 lntra- 135 25 I40 7 36 8(2) l9 venous v lntra- 160 O l80 0 65 +70( 10) 40 +40( 10') 24 (3+2) venous 5 lntra- 160 +l2 I90 13 2S +l40(5') -53 +50(5') -37 (3+2) venous l0 lntra- 200 -10 230 15 60 +25(5') 20 12 +2705) -20 duodenal TABLE III Dose Method of AP. Flow of the femoral artery Flow of the cerebral artery mg/kg administration Value ml/min A Duration in Value ml/min A Duration in max minutes. max minutes 5 Perfusion IV, 0 40 100 5 mins 12 33 5 mins for 5 minutes 6 Perfusion IV, 40 200 5 mins 20 125 5 mins for 6 minutes 12 Perfusion IV, 0 133 5 mins 20 75 5 mins for l2 minutes 3O Weclatm: 2. An aminoketone according to claim 1 whereln the 1. An aminoketone of the formula: acid addition salt is a salt of hydrochloric, hydrobromic, hydroiodic, sulphuric, phosphoric, oxalic, fu- QR maric, maleic, malic, citric, ascorbic, cyclohexylsul- 35 phamic benzoic, glutamic or aspartic acid.

3. (2,4,6-Trimethoxyphenyl)( 3- R10 m pyrrolidinopropyl)ketone or a non-toxic acid addition salt thereof. 4. (2,4,6-Triethoxyphenyl;)(3-

4 pyrrolidinopropyl)ketone or a non-toxic acid addition wherein each of R R and R are the same or different, and represent methyl or ethyl, and n is 3. or a nontoxic acid addition salt thereof.

'salt thereof. 

1. AN AMINOKETONE OF THE FORMULA:
 2. An aminoketone according to claim 1 wherein the acid addition salt is a salt of hydrochloric, hydrobromic, hydroiodic, sulphuric, phosphoric, oxalic, fumaric, maleic, malic, citric, ascorbic, cyclohexylsulphamic benzoic, glutamic or aspartic acid.
 3. (2,4,6-Trimethoxyphenyl)(3-pyrrolidinopropyl)ketone or a non-toxic acid addition salt thereof.
 4. (2,4,6-Triethoxyphenyl)(3-pyrrolidinopropyl)ketone or a non-toxic acid addition salt thereof. 